Irritant composition comprising certain substituted formanidines

ABSTRACT

WHEREIN R1 is alkyl, cycloalkyl, bicycloalkyl, or tricycloalkyl, R2 is hydrogen or alkyl, R3 is alkyl, and R4 is alkyl and can be joined with R3 to form a saturated ring. Typical is N,N-dimethyl-N&#39;&#39;-(4-cyclohexylmethylcyclohexyl)formamidine useful for repelling animals.   Repelling animals with cyclohexylformamidines of the formula:

United States Patent Knowles 1 Sept. 5, 1972 {54] IRRITANT COMPOSITIONCOMPRISING CERTAIN SUBSTITUTED FORMANIDINES [52] U.S. Cl ..424/32 6,260/564 R, 424/244, 424/267, 424/274 [51] Int. Cl. ..A01n 9/20, A0ln9/22 [58] Field of Search ..424/326, 244, 267, 274; 260/564 56 IReferences Cited I UNITED STATES PATENTS 3,228,975 1/1966 Geldlum et a]...424/3 26 3,109,845 1 1/1963 Seeger et a1. ..424/274 PrimaryExaminer-Leland A. Sebastian Attorney-l-lerbert W. Larson [57] ABSTRACTRepelling animals with cyclohexylformamidines of the formula:

wherein R is alkyl, cycloalkyl, bicycloalkyl, or tricycloalkyl, R ishydrogen or alkyl, R is alkyl, and R is alkyl and can be joined with Rto form a saturated ring. Typical isN,N-dimethyl-N'-(4-cyclohexylmethylcyclohexyl)-fonnamidine useful forrepelling animals.

8 Claims, No Drawings IRRITANT COMPOSITION COMPRISING CERTAINSUBSTITUTED FORMANIDINES CROSS REFERENCE This application is adivisional of my copending application Ser. No. 634,037, filed Apr. 20,1967.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION I have discoveredthat animal repellant activity is shown by the following compounds:

wherein R is alkyl of three through eight carbon atoms, cycloalkyl offour through nine carbon atoms, cycloalkylalkyl of five through carbonatoms, bicycloalkyl of seven through 10 carbon atoms or tricycloalkyl of10 through 11 carbon atoms,

R is hydrogen or alkyl containing one through three carbon atoms,

R is alkyl containing one through four carbon atoms, and

R is alkyl containing one through four carbon atoms and can be joinedwith R to form a saturated hydrocarbon ring. 4

The dotted line in formula 1 denotes those compounds where R and R arejoined.

Preferred because of excellent animal irritant activity at low rates ofapplication are those compounds of formula 1 wherein R is hydrogen and Rand R are not joined.

(III).

Particularly preferred because of outstanding animal irritant activityat low use rates are the cis and trans isomers ofN,N-dimethyl-N-(4-cyclohexylmethylcyclohexyl)formamidines.

UTILITY Compounds of this invention cause potent irritation to animaltissue, particularly to the mucous membranes.

Animals exposed to the above compounds show signs of severe respiratoryirritation. These compounds have two advantages over currently used riotcontrol agents such as ortho-chlorobenzylidenemalonitrile (CS) and2-chloroacetophenone (CN) as well as over currently used animalrepellants such as dried blood for deer, allylisothiocyanate for dogsand zinc dithiocarbamateamine complex for rodents. One, the compoundsare more potent at low concentrations and two, provide residual activityover longer periods of time.

Compounds of this invention andparticularly cis/trans mixtures ofN,N-dimethyl-N'-(4-cyclohexylmethylcyclohexyl)formamidine have potentialuse as riot control agents, dog repellants, deer repellants, rodentrepellants and for contaminating caves 'or underground tunnels.

PREPARATION The compounds of this invention are prepared by the reactionof an amine with an amide diethylacetal. This reaction is illustratedbelow. R,, R R and R are as defined in formula 1 The amidediethylacetals and formamidines are prepared according to the method'ofI-l. Bredereck, F. Effenberger and G. Simchen; Angew. Chem, 73, 493(1961).

The desired formamidine is prepared by refluxing an amine with the amidediethylacetal according to Reaction I for one to two hours, and then thesolution is distilled. The first cut consists of ethanol; theformamidine is then distilled at reduced pressure. The amineintermediates can be prepared according to the following syntheticroute.

R is as defined in formula (1 The Friedel Crafts reaction (II) is run bycarefully adding the acid chloride to a stirring mixture of aluminumchloride in benzene. A slight molar excess of catalyst is used; benzeneserves as both-a solvent and reactant. The acid chloride is added at arate so as to keep the temperature of the slurry at about 30-40C. Themixture is stirred for 1 additional hour after all of the acidchlorideis added, and then water is slowly added to decomposethe catalyst.Sufficient water is added so that all the solids are dissolved. Thephenylalkylketone is isolated from the benzene solution and is purifiedby distillation.

The Wolff-Kishner reduction (III) is run in 2-(2- ethoxyethoxy)ethanolusing a modification of the procedure given by J. Cason et al. inOrganic Synthesis, Collective Volume IV, John Wiley and Sons, New York,(1963), p. 510. Once the reactants are mixed, they areheated to refluxfor a period of 3 to 5 hours. The reflux temperature is generally in the130-140C. range. After completion of the reflux period, the solution iscooled and poured into 3 to 4 volumes of water. The alkylbenzene productis extracted with pentane, and purified by distillation.

cis

The F riedel-Crafts reaction (IV) is run by mixing approximately'equimolar quantities of the reactants together in hexane ornitromethane at less than 5C. The stirring mixture is slowly allowed towarm to room temperature, and after hydrogen chloride evolutionsubsides, the mixture is refluxed several hours. Water is then addedslowly to decompose the catalyst. A sufficient quantity of water is thenadded so that all of the solids are dissolved. The desired acetophenonederivative isisolated from the organic phase and purified bydistillation. Gas-liquid chromatography on an F & M Model 500 GasChromatograph using a 2 feet X V4inches O.D. stainless steel column,containing 10 percent Carbowax 20M on 60-80 mesh Diatoport T indicatesthat about 98 percent of the acetophenone is the 1,4-isomer and 2percent is the 1,2-isomer. The 1,2- isomer has the shorter retentiontime.

The haloform reaction (V) is run by slowly adding a cold 5C.) sodiumhypochlorite solution to a stirring solution of the acetophenonederivative in methanol. This is a modification of the procedure used byE. E. Royals, Journal American Chemical Society, Volume 69, p. 841(1947), for the haloform reaction of a-ionone. After the sodiumhypochlorite solution is added, the mixture is warmed to roomtemperature, and left standing over night. The mixture is heated toreflux, and the distillate collected until the pot temperature rises to95-97C.; most of the methanol is distilled. The pot is then cooled toroom temperature.

In those reactions where R, does not have a large molecular weight, suchas cyclobutyl, the sodium benzoate derivative remains dissolved;however, when R is of a larger molecular weight, such as n-octyl, thesodium benzoate derivative precipitates as a soapy solid. Sulfur dioxideis bubbled into the alkaline pot concentrate until the pH drops below 3.The precipitated benzoic acidderivative is either filtered and washedwith water, or extracted with methylene chloride depending on whether ornot the benzoic acid is easily filterable or is of a soapy nature. Someof these benzoic acid derivatives can be recrystallized fromacetonitrile or pentane, and some are purified merely by triturationwith cold pentane.

The catalytic hydrogenation (VI) is performed at 1 to 4 atmospheres-ofhydrogen using platinum oxide as catalyst and glacial acetic acid assolvent. {A Parr Hydrogenation Apparatus is suitable for thesereactions. This reaction produces a cis/trans isomer mixture of about 2or 3 to l. The cis and trans designation refers to the relationship ofthe 4-alkyl substituent and carboxylic acid group on the cyclohexanering; this is illustrated below.

E 211 I H 002E RiC 2 trans The Schmidt reaction (Vll) is performed bydissolving the cyclohexane carboxylic acid derivative in a mixture ofchloroform and concentrated sulfuric acid. Sodium azide is then added insmall portions to the stirring mixture at a rate sufficient to keep thereaction temperature between 35 and 45C. The mixture is stirred at about45 to 50C. until the bubbling nearly stops (1 to 3 hours). The mixtureis then transferred to a separatory funnel, and the lower, gelatinoussulfuric acid layer is slowly dripped into ice. The amine sulfateprecipitates as a soapy material which slowly crystallizes. Thechloroform should be kept away from the ice water mixture since it makesthe work-up much more difficult. Those amines which crystallize as thehemisulfates or sulfates are filtered and washed with water. It isconvenient to store the amines as their salts. Those amine salts whichfail to crystallize are converted to the free bases by making thesulfuric acid solution alkaline, and extracting the amine withdichloromethane. The

amine is then purified by distillation. The Schmidt reacstituted anilinederivatives are available. This route is illustrated below.

COMPOSITIONS with an inert diluent non-toxic to animals. The diluentselected depends on the route of administration.

Emulsifying agents can be used with the diluent and compound of formula1 to aid in dispersion of the active ingredient. Emulsifying agents thatcould be used include alkylaryl polyethoxy alcohols, alkyl and alkylarylpolyether alcohols, polyoxyethylene sorbitol or sorbitan fatty esters,polyethylene glycol fatty esters, fatty alkylol amide condensates, aminesalts of fatty alcohol sulfates plus long chain alcohols and oil solublepetroleum sulfonates.

The amount of emulsifying agent in the composition will range from 0.1to 20 percent by weight. I

Since the compounds of the present invention would generally beadministered by vapor or spray application, the compositions willcontain a liquid diluent such as water, acetone, hexane, gasoline,kerosene, other hydrocarbon oils, alcohols or other liquids generallyused in pharmaceutical preparations.

The amount of active ingredient in the composition will vary from 0.005percent by weight to 95 percent or even higher. The diluent willgenerally constitute the major proportion of the composition and theamount of active ingredient will be less than 50 percent by weight. Theexact concentration of the active ingredient will depend on themechanism used for administration and will be easily understood by oneknowledgeable in pharmaceutical application rates.

APPLICATION A quantity of active ingredient sufficient to causeirritation to animal tissue is 100 to 6,000 micrograms per liter of airat exposure of 1 minute. It is expected that this rate applies to allanimals. Rates of over 6,000 micrograms per liter of air at exposure ofone minute kill 50 percent of the mice which are treated.

The following additional examples are provided to more particularlyexplain the invention.

EXAMPLE 1 A solution of 10.6 g. (54m moles) of4-cyclohexylmethylcyclohexylamine and 8.1 g. (55m mole) ofdimethylformamide diethylacetal is refluxed for 1% hours in a 50 ml.round bottom flask. The ethanol is then distilled; about 3.8 ml. ofethanol is collected. The oil remaining in the pot is then distilled invacuum. The N ,N-dimethy1N-(4-cyclohexylmethylcyclohexyl)formamidineboils at 123C. at a pressure of 0.3 mm. of mercury ([1025 1.5010). v

Gas-liquid chromatography on an F & M Model 500 Gas Chromatograph usinga 2 feet X firinches O.D. stainless steel column packed with percentCarbowax M on 60-80 mesh Diatoport at a column temperature of 225C.,block temperature of 312C, injection port temperature of 280C, and ahelium flow rate of 60 cc./min. separates the cis and trans isomers. The

cis and trans isomers have retention times of 10.5

minutes and 13.0 minutes respectively and are present in the ratio ofabout 4 to 1.

Anal. Calcd. for C H N C, 76.7; H, 12.1; N,

Found: C, 76.6; H, 12.0; N, 11.3%.

Mice are treated by aerosol exposure to this cis/trans mixture ofN,N-dimethyl-N-(4-cyclohexylmethylcyclohexylformamidine in the followingmanner: The compound is administered as an aerosol into a 2.8 literchamber. The exposure chamber consists of a 2.8 liter bell jar over anebullizer inserted through the floor of the chamber. Mice are exposedfor 5 minutes to 350 micrograms per liter of air (1,750 Ct). Thecompound is dissolved in 1.4 ml. of acetone and during a span of 20seconds the compound is sprayed up into the chamber. No further air istransferred into or out of the chamber during the 5 minute exposure.

After this exposure, irritant effects are observed in all mice exposed,but not in controls exposed to 1.4 ml. of acetone alone. Irritanteffects can be described as the presence of one or more of the followingreactive signs:

a. abnormal gait, including rubbing of the nose on the floor whilerunning about b. depression c. dyspnea.

EXAMPLES 2 15 The following compounds are made in a manner like that ofN,N-dimethyl-N'-(4-cyclohexylmethylcyclohexyl)-formamidine of Example 1by substituting a like amount by weight of the appropriate amine andamide diethylacetal for the 4-cyc1ohexylmethylcyclohexylamine anddimethylformamide diethylacetal of Example 1. They produce like irritanteffects.

2. N,N-diethyl-N'-(4-n-hexylcyclohexyl)formamidine.

3. N,N-dipropyl-N'-[4-( 2-[2.2.1]-bicycloheptylmethyl)-cyclohexyl]formamidine.

4. N,N-dibutyl-N'-[4-iso-butylcyclohexyl]formamidi 5.N,N-dimethyl-N'-[4-cyclopentylmethylcyclohexyl]acetamidine.

. N,N-dimethyl-N 4-( 3-cyclopentylpropyl)cyclohexyl]-formamidine.

7. N ,N-dimethyl-N'-[4-n-octylcyclohexyl]butyramid 8. N,N-dimethyl-N'-[4-( l-adamantylmethyl)cyclohexyl]formamidine.

9. i N ,N-pentamethylene-N 4-cyclobutylmethylcyclohexyl)-formamidine.

10. N,N-dimethyl-N 4-n-butylcyclohexyl )formamidine.

1 l. N,N-tetramethylene-N'-(4-cyclohexylmethylcyclohexyl)-formamidine.

1 2. N,N-dimethylene-N'-(4-n-hexylcyclohexyl)acetamidine.

l3. N,N-octamethylene-N'-(4-n-butylcyclohexyl)formamidine.

l4. N,N-dimethyl-N-(4-[3-cyclopentylpropyl]cyclohexyl)-formamidine.

15. N-N-Dimethyl-N-(4-cycloheptylmethyl)formamidine.

7 EXAMPLE 16 A 2 percent solution of N,N-dimethyl-N'-(4-cyclohexylmethylcyclohexyl)formamidinc in dichloromethane is di spersedv as an aerosol into and through a chamber containing young adult maleguinea pigs weighing 250-300 grams. This aerosol is generated by feedingthe solution of test compound througha commercial paint sprayer jet atthe rate of ml./min., and dispersing the spray with a stream of airhaving a flow rate of 44 liters/min. supplied at a pressure of 62pounds/sq. inch. The efficiency of forming respirable particles rangesfrom 10 to 40 percent. This aerosol gives a concentration ofN,N-dimethyl-N-( 4-cyclohexylmethylcyclohexyl)formamidine in the chamberof 2.1 mgJliter. The particles in the aerosol have a mass mediandiameter of 1.3 microns with a standard geometric deviation of 2.0microns.

The guinea pigs exposed to this aerosol for one minute experienceddyspnea characterized by a coughlike spasm which lasts for 2 hours. Theguinea pigs also tried to escape from the chamber and exhibited facepawing. No adverse effects are seen 24 hours after the exposure.

I claim:

1. An animal irritant composition comprising a major amount of an inertliquid diluent non-toxic to animals and an amount sufficient tocauseirritation to animal tissue of a compound of the formula:

wherein R is selected from the group consisting of alkyl of threethrough eight carbon atoms, cycloalkyl of four through nine carbonatoms, cycloalkylalkyl of five through 10 carbon atoms, bicycloalkyl ofseven through 10 carbon atoms and tricycloalkyl of 10 through 11 carbonatoms,

R is selected from the group consisting of hydrogen and alkyl containingone through three carbon atoms,

R is alkyl containing one through four carbon atoms, and

R is alkyl containing one through four carbon atoms; and R and R, can bejoined to form a satu- 8 rated hydrocarbon ring containing two througheight carbon atoms.

2. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, a compound of the formula:

wherein R is selected from the group consisting of alkyl of threethrough eight carbon atoms, cycloalkyl of four through nine carbonatoms, cycloalkylalkyl of five through 10 carbon atoms, bicycloalkyl ofseven through 10 carbon atoms and tricycloalkyl of l0through ll carbonatoms,

R, is selected from the group consisting of hydrogen and alkylcontaining one through three carbon atoms,

R, is alkyl containing one through four carbon atoms, and

R is alkyl containing one through four carbon atoms; and R and Rl can bejoined to form a saturated hydrocarbon ring containing two through eightcarbon atoms.

3. Method of repelling animals according to Claim 2 wherein R in thecompound applied is .cyclohexyl.

4. Method of repelling animals according to Claim 2 wherein R in thecompound applied is hydrogen.

5. Method of repelling animals according to Claim 2 wherein R and R areboth methyl in the compound applied.

6. Method of repelling animals according to Claim 2 wherein R iscyclohexyl and R is hydrogen in the compound applied.

7. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, N,N-dimethyl-N-(4-cyclohexylmethylcyclohexyl)formamidine.

8. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, N,N-'

dimethyl-N'-( 4-n-butylcyclohexyl)formamidine.

2. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, a compound of the formula:
 3. Method of repelling animalsaccording to Claim 2 wherein R1 in the compound applied is cyclohexyl.4. Method of repelling animalS according to Claim 2 wherein R2 in thecompound applied is hydrogen.
 5. Method of repelling animals accordingto Claim 2 wherein R3 and R4 are both methyl in the compound applied. 6.Method of repelling animals according to Claim 2 wherein R1 iscyclohexyl and R2 is hydrogen in the compound applied.
 7. Method ofrepelling animals comprising applying to an area to be protected fromanimals in an amount sufficient to cause irritation to animal tissue,N,N-dimethyl-N''-(4-cyclohexylmethylcyclohexyl)formamidine.
 8. Method ofrepelling animals comprising applying to an area to be protected fromanimals in an amount sufficient to cause irritation to animal tissue,N,N-dimethyl-N''-(4-n-butylcyclohexyl)formamidine.